tbuckley/cabot-search huggingface dataset:
Bcl-xL and association with apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer.
Authors: Hajrah Khawaja, Rebecca Briggs, Cheryl Latimer, Md A.M.B Rassel, Daryl Griffin, Lyndsey Hanson, Alberto Bardelli, Federica Di Nicolantonio, Simon McDade, Christopher Scott, Shauna Lambe, Manisha Maurya, Andreas Ulrich Lindner, Jochen HM Prehn, Jose Sousa, Chris Winnington, Melissa J LaBonte, Sarah Ross, Sandra Van Schaeybroeck
Journal: Journal of Clinical Oncology (2022)

3557 Background: Novel covalent inhibitors of KRAS G12C have shown modest response rates in KRAS G12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRAS G12C inhibitor combination strategies that can achieve deep and durable responses are needed. Methods: The small molecule KRAS G12C inhibitors AZ’1569 and AZ’8037 were employed. To identify novel candidate combination strategies for AZ’1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRAS G12C MT CRC cells and in vivo xenograft models. AZ’1569 acquired resistant CRC models were generated and characterised. Results: Response to AZ’1569 was heterogeneous across the KRAS G12C MT models. AZ’1569 was ineffective at inducing apoptosis when used as a single agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as top hit mediating resistance to AZ’1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ’1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569 in a panel of KRAS G12C MT CRC cells. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRAS G12C MT CRC xenografts. Finally, AZ’1569 acquired resistant KRAS G12C MT CRC cells showed amplification of KRAS G12C , EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to standard-of-care chemotherapy and several targeted agents. Importantly, the KRAS amplification and AZ’1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Conclusions: Combinatorial targeting of Bcl-xL and KRAS G12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12C MT CRC patients. The cross-resistance to other targeted therapies and importantly conventional chemotherapy in the AZ’1569 acquired resistant cells poses a challenge, with implications for the optimal use of KRAS G12C inhibitors as a second or third line option.
QOL-31. A psychosocial support program for young adult childhood cancer survivors in Austria: a qualitative evaluation study
Authors: Thomas Pletschko, Kerstin Krottendorfer, Juliana Schlifelner, Agathe Schwarzinger, Verena Fohn-Erhold, Liesa Weiler-Wichtl, Anita Kienesberger, Ulrike Leiss
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: Many adolescents and young adult (AYAs) childhood cancer survivors face disease- or therapy-related late-effects, which limit their participation in various areas of daily life. AYAs are often left alone in our health care system and many worry about their ability to cope with long-term sequelae and some are even lost to follow up. Therefore, in the present study a targeted aftercare program was developed and evaluated with the goal of facilitating three important “life skills”: (1) self-perception, (2) social interaction and conflict management as well as (3) self-conscious communication of support needs. METHODS: A total of n=13 participants (19.2-30.2 years, mean age: 22.8 years) completed a three-day aftercare seminar, at the end of which each participant wrote a reflection letter (“letter to my future self”), elaborating on observed effects of the seminar, applicability of the given information in daily life and the direct impact of the seminar on their individual circumstances. The reflection letters were analyzed using qualitative content analysis. RESULTS: All target life skills were mentioned in the reflection letters. The participants reported individual benefits from the program especially with respect to self-perception and self-confidence, giving and taking feedback, and acceptance of personal strengths and weaknesses. Moreover, the feeling of “not being alone” was associated with the survivors’ experience of emotional and social support. CONCLUSIONS: This evaluation highlights the potential of a one weekend aftercare seminar to address important life skills that are known to positively influence health behavior in AYAs. The detailed description of the seminar can serve as a basis for making this kind of aftercare accessible for other people in similar circumstances.
SWK-01. Partnership between caregivers, patients and healthcare professionals: promoting collaboration in a complex care pathway in pediatric neuro-oncology
Authors: Anita Granero, Anne Isabelle Bertozzi, Eloise Baudou, Kathy Oliver
Journal: Neuro-Oncology (2022)

Abstract Children with a brain tumor and their families encounter, from the moment of diagnosis, a complex, multidisciplinary and multisite journey. Oscar's Angels (OA) is an association of trained patient advocate volunteers within a hospital structure who provide daily support to pediatric neuro-oncology patients and their families in complex care pathways. The association promotes collaboration in healthcare by facilitating a strong link between the daily reality of patients and their families and that of the hospital. OA volunteers are active and fully accepted members of the hospital multi-disciplinary team and collaborate on a very high level in the care of pediatric patients. Such a collaborative setting is possible because the work of OA is structured around three principles: Innovative, practical and theoretical initial and ongoing training and quality assessment of volunteers Patient and family support from Oscar’s Angels volunteers throughout the care pathway Government certification, institutional representation and active collaboration in educating healthcare professionals about the importance of patient advocacy and patients’ needs Operating in France since 2001 and in Italy since 2017 (with more than 600 and 200 families respectively supported last year), the OA volunteering program is specifically tailored to the needs and demands of hospitals and families. It can therefore be successfully reproduced in many settings. OA’s services come at no cost to hospitals. This is particularly important for implementing the program in developing countries where healthcare resources are extremely limited. But it is also relevant in developed countries as well where healthcare budgets are under strain. In 2020 an informal internal OA survey highlighted that the patient/family/volunteer/healthcare professional interface provides added value for all of these stakeholders. A formal survey will be conducted in 2022 to corroborate these results.
Configuration and validation of the Toronto nomogram of antenatal ultrasound index generated from Bayesian meta-regression analysis in predicting Posterior Urethral Valves (PUV)
Authors: J.K.J. Kim, M. Chua, T. Van Miegham, J. Dos Santos, E. Mackay, L. Erdman, M. Skreta, D. Keefe, M. Lolas, P. Yadav, A. Lorenzo, M. Rickard
Journal: European Urology (2022)
Energy density in high-power (100w) holmium laser enucleation of the prostate (holep) -retrospective analysis of procedural, and functional outcomes among 1,515 patients
Authors: P. Gild, K.B. Breunig, M.W. Vetterlein, T.A. Ludwig, A. Soave, P. Marks, R. Dahlem, M. Fisch, M. Rink, C.P. Meyer
Journal: European Urology (2022)
Patients with cancer symptom and physical function reporting by caregivers as predictors of adverse clinical outcomes.
Authors: Elad Neeman, Reem Yunis, Ai Kubo, Sara Aghaee, Jennifer Shieh, Tess L Veuthey, Stephanie Jo Fonda, Raymond Liu, Ingrid Oakley-Girvan
Journal: Journal of Clinical Oncology (2022)

12026 Background: Informal caregivers are essential partners in the delivery of cancer care, and often can accurately identify and report symptoms and physical function of the patients they care for. We assessed whether such reporting by caregivers is predictive of adverse patient outcomes. Methods: In this prospective study, adult solid cancer patients on active intravenous systemic therapies and their informal caregivers were recruited from 18 Kaiser Permanente Northern California cancer centers. Using a study mobile app (TOGETHERCare), caregivers completed weekly surveys for 4 weeks, which were based on normalized NIH-PROMIS scores to report patients’ physical function and PRO-CTCAE to report patients’ symptoms. Patients’ adverse clinical outcomes were abstracted from the medical record and included: emergency department (ED) visits or hospitalizations, grade 3-4 adverse events (AEs), and treatment delays, up to 1 month following the 4-week study period, as well as mortality and hospice referrals up to 6 months following the study period. Simple univariate logistic regressions were used to correlate caregiver reports (either at baseline or most proximal preceding an adverse outcome) with mortality and hospice referrals, and quasi-Poisson regressions were used for the other adverse outcome measures. Results: Fifty-four patient-caregiver dyads were enrolled, and 52 were included in this analysis. A third of patients had breast cancer and almost 75% had stage 3 or 4 disease. Caregivers predominantly identified as male (61.5%), spouse/partner (76.9%), and non-Hispanic White (63.5%). At least one adverse outcome was experienced by 36.5% of the patients. Caregiver-reported PRO-CTCAE consistently predicted ED/hospitalizations and mortality, and caregiver-reported PROMIS scores predicted hospice referrals (see Table). Conclusions: The results suggest that caregiver reporting of patients’ symptoms and physical function could help provide early predictions of adverse patient outcomes.[Table: see text]
Disparities in cancer-specific mortality between Asian and Caucasian patients with non-metastatic renal cell carcinoma: Analysis of the INMARC registry
Authors: H. Tanaka, S. Fukuda, Y. Yasuda, D. Patil, A. Saidian, A. Walia, M. Meagher, J. Perry, M. Nguyen, R. Narasimhan, S. Yoshida, M. Yokoyama, Y. Matsuoka, V.A. Master, I.H. Derweesh, K. Saito, Y. Fujii
Journal: European Urology (2022)
Multicenter validation of the diagnostic accuracy of multiparametric magnetic resonance imaging to detect residual prostate cancer in the follow-up of focal therapy with irreversible electroporation
Authors: B. Geboers, W. Gondoputro, J. Thompson, D.J. Reesink, L.A.M.J.G. Van Riel, D. Zhang, A. Blazevski, P. Doan, S. Agrawal, J. Mathews, A-M. Haynes, Z. Liu, W. Delprado, R. Shnier, T. De Reijke, N. Lawrentschuk, P.E.F. Stijns, J. Yaxley, M. Scheltema, P. Stricker
Journal: European Urology (2022)
Comparison of low-dose-rate brachytherapy versus radical prostatectomy in patients with intermediate-risk prostate cancer: A propensity-matched multi-institutional study
Authors: H. Tsumura, N. Tanaka, T. Oguchi, T. Owari, Y. Nakai, I. Asakawa, K. Iijima, H. Kato, I. Hashida, K. Tabata, T. Satoh, H. Ishiyama
Journal: European Urology (2022)
Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets
Authors: Michael H. Guo, Prashanth Sama, Brenna A. LaBarre, Hrishikesh Lokhande, John Balibalos, Ci Chu, Xiaomi Du, Pouya Kheradpour, Charles C. Kim, Taylor Oniskey, Thomas Snyder, Damien Z. Soghoian, Howard L. Weiner, Tanuja Chitnis, Nikolaos A. Patsopoulos
Journal: Genome biology (2022)

Abstract Background Multiple sclerosis (MS) is an autoimmune condition of the central nervous system with a well-characterized genetic background. Prior analyses of MS genetics have identified broad enrichments across peripheral immune cells, yet the driver immune subsets are unclear. Results We utilize chromatin accessibility data across hematopoietic cells to identify cell type-specific enrichments of MS genetic signals. We find that CD4 T and B cells are independently enriched for MS genetics and further refine the driver subsets to T h 17 and memory B cells, respectively. We replicate our findings in data from untreated and treated MS patients and find that immunomodulatory treatments suppress chromatin accessibility at driver cell types. Integration of statistical fine-mapping and chromatin interactions nominate numerous putative causal genes, illustrating complex interplay between shared and cell-specific genes. Conclusions Overall, our study finds that open chromatin regions in CD4 T cells and B cells independently drive MS genetic signals. Our study highlights how careful integration of genetics and epigenetics can provide fine-scale insights into causal cell types and nominate new genes and pathways for disease.
Dorsal onlay oral mucosa graft urethroplasty for female urethral stricture
Authors: C. Richard, B. Peyonnet, A. Drain, J. Hascoet, N. Rosenblum, R.D. Sussman, L. Freton, L.C. Zhao, V.W. Nitti, B.M. Brucker
Journal: European Urology (2022)
Variants of unknown significance (VUS) in patients with hereditary CRC without a known pathogenic variant.
Authors: Marija Stojovska, Nadica Matevska-Geshkovska, Elizabeta Krstevska Bozhinovikj, Biljana Grozdanovska, Nenad Mitrevski, Aleksandar Dimovski
Journal: Journal of Clinical Oncology (2022)

10599 Background: Nearly 5-10% of all newly diagnosed colorectal cancer (CRC) cases develop due to the presence of a highly penetrant pathogenic variant in one of the hereditary colorectal cancer (hCRC) associated genes. NGS technology raised the opportunity for fast and efficient detection of these variants, but still in ̃20-30% of patients with hCRC the genetic defect remains unknown. Recent data shows that 6-8% of these cases harbor pathogenic/VUS variant in low/moderate penetrance genes not directly associated with hCRC. Methods: A total of 109 patients with hCRC (43 with polyposis and 66 with non-polyposis syndromes) were analyzed by NGS covering coding and exon/intron sequences of 109 genes, of which 25 associated with known hCRC syndromes and 83 other cancer predisposition genes. Results: Pathogenic variants were detected in 63/109 (57.7%) of analyzed patients; 54/63 (85.7%) of these had a pathogenic variant in one of the genes associated with hCRC (APC, MMR genes, MUTYH, NTHL1, BMPR1A) and 9/63 (14.3%) had a pathogenic variant detected in genes not directly related to hCRC (CHEK2, FANCL, FANCM, ERCC2, BRIP1, FLCN, BLM). In 26/109 (23.8%) patients a rare VUS variant was detected, of which 14/26 (53.8%) in double strand repair (DRG) genes (BLM, CHEK2, PALB2, ATM, MRE11A, BRIP1, FANCM, FANCL and ERCC2), 8/26 (30.8%) in one of the known hCRC genes (APC, MSH6, PMS2 and POLE) and 4/26 (15.4%) in other cancer predisposition genes (KIT, NSD1, CDH1, EZH1 and FH). VUS variants in DRG genes were more common in patients with MSI- HNPCC (9/15, 60%), compared to patients with polyposis syndromes (6/15, 40%). The VUS variants in other cancer predisposition genes were dominantly present in patients with oligopolyposis. Most (21/26, 80.8%) VUS variants were detected as single variants, while only five patients (5/26, 19.2%) had two different variants in two different genes. In 20/109 (18.3%) patients who presented primarily with MSI- HNPCC or oligopolyposis phenotypes, no pathogenic and/or VUS variants were detected in the 109 analyzed genes. Conclusions: Genetic basis of hereditary CRC was not clearly defined in a large proportion (42.3%) of patients in our cohort. Although a VUS variant was detected in a significant portion (23.8%), a major fraction (18.3%) of patients had no known genetic variant detected. The presence of a high frequency of VUS variants in DRG genes indicates that this pathway plays an important role in CRC carcinogenesis. Although we cannot exclude the presence of deep intronic and/or regulatory region pathogenic variants in the analyzed genes, it appears that the current list of identified cancer predisposition genes responsible for the hereditary CRC is far from being complete. The influence of environmental factors in conjunction with polygenic inheritance might also play a key role in a fraction of hCRC in our population.
Oncological outcomes, patterns of recurrence and impact of competing causes of mortality in clinically node-positive prostate cancer patients treated with radical prostatectomy
Authors: G.O. Cirulli, D. Robesti, G. Gandaglia, V. Cucchiara, R.J. Karnes, G. Devos, C. Berghen, W. Evaraerts, S. Joniau, A. Pellegrino, G. Rosiello, R. Leni, M. Tutolo, M. De Angelis, A. Gallina, N. Fossati, F. Dehò, H. Van Poppel, F. Montorsi, A. Briganti
Journal: European Urology (2022)
The emerging fifth epidemiologic subtype of Kaposi sarcoma in HIV-negative men who have sex with men at a tertiary care center in NYC from 2000 to 2021.
Authors: Ayana E Morales, Gabrielle Benson, Stephanie Glavan, Rosemary Giuliano, Mark Andrew Dickson
Journal: Journal of Clinical Oncology (2022)

11579 Background: Kaposi sarcoma (KS) is a vascular tumor caused by human herpesvirus 8, also known as Kaposi sarcoma herpesvirus. There are 4 widely accepted distinct epidemiologic subtypes of KS: classic, endemic, iatrogenic, and epidemic (HIV-associated) forms. An emerging 5 th subtype is increasingly recognized: non-epidemic KS in men who have sex with men (MSM) who are HIV-negative and have no other known causes for immunodeficiency. Objectives: To characterize a cohort of non-epidemic KS seen at the Sarcoma Medical Oncology or Dermatology Clinics at Memorial Sloan Kettering Cancer Center in New York City from 2000 to 2021 to identify risk factors, presentation, treatment course, and prognosis of these patients. Methods: Following IRB approval, a retrospective observational study was performed. Eligible patients were identified through the Electronic Health Records (EHR). The patients were characterized based on age at presentation, sex, gender identity, comorbidities, coinfections, and treatments and outcomes amongst other factors. Study data were collected and managed using REDCap electronic data capture tools. Results: Seventy-two patients were identified. The median age at time of diagnosis was 58 (range: 32-83). At initial diagnosis, 46% (33/72) of patients underwent observation, 50% (36/72) received localized treatment (i.e. excision, cryotherapy or topical therapy), and 4% (3/72) received systemic treatment with chemotherapy. The median duration of follow-up was 22 months. In follow-up, 43% (31/72) of patients had progression of disease requiring recurrent treatment: 24% (17/72) received localized treatment while 18% (13/72) received chemotherapy. Patients who received chemotherapy, predominantly pegylated liposomal doxorubicin, received treatment for a median duration of 13 months (range: 2-72 months). By the end of the follow-up period, 7 patients had died, of which 2 deaths were attributed to KS. During follow up, 10% (7/72) of patients were diagnosed with a lymphoproliferative disorder. Conclusions: This study is the largest yet, to our knowledge, to characterize the non-epidemic KS subtype in HIV-negative MSM. It is important to recognize this KS subtype to identify these individuals, who despite not having HIV are at increased risk for KS. Accurate recognition of this subtype may also allay patient concerns regarding overall prognosis, given that the majority of these patients present with indolent disease and have favorable outcomes compared to the epidemic variant of KS. Additional research is needed to understand the potential increased risk of lymphoproliferative disorders.
The effect of age on cancer-specifc mortality in T1a stage renal cell carcinoma patients: A population-based study across all treatment’s modalities
Authors: A. Pecoraro, S. Knipper, C. Palumbo, G. Rosiello, S. Luzzago, M. Deuker, Z. Tian, S.F. Shariat, F. Saad, A. Briganti, A. Kapoor, S. De Cillis, A. Piana, F. Piramide, M. Sica, D. Amparore, E. Checcucci, M. Manfredi, C. Fiori, F. Porpiglia, P.I. Karakiewicz
Journal: European Urology (2022)
Impact of equal access by race and ethnicity on patients in the Veterans Health Administration (VHA) treated for diffuse large B-cell lymphoma (DLBCL).
Authors: Snegha Ananth, Alaq Al-Abayechi, Jean-Pierre Blaize, Lauren Boyle, Raissa Lakene Djoufack Djoumessi, Manuel Ricardo Espinoza Gutarra, Kathleen Franklin, Lindsey Lu, Kana Lucero, Michael Mader, Phillip Nazarewicz, Zohra Nooruddin, Abhishek Pandya, Gabriel Roman Souza, Michael Meansup Song, Brian Warnecke, Jennifer Whitehead, Madison H. Williams, Ryan A. Williams
Journal: Journal of Clinical Oncology (2022)

6526 Background: Racial and ethnic disparities in access to care and outcomes are well-established and are critical issues across several malignancies, including DLBCL. Previous studies from national registry datasets have shown racial disparities in DLBCL disease characteristics, treatment and outcomes. The VHA is an equal access system providing a unique environment to investigate cancer disparities across the disease continuum. Methods: This is a retrospective chart review of 4033 randomly selected patients with an ICD code for lymphoma treated within the VHA between 01/01/2011 and 12/31/2017. Data abstractors collected baseline patient and disease characteristics and treatment responses for those with an initial diagnosis of DLBCL in that time frame. Survival time was determined via electronic health record query on 11/30/2021. Chi-square tests were used to analyze relationship between race and variables of interest. Cox proportional hazards model was used to estimate hazard ratios (HR) for race and controlling factors. Results: 2141 DLBCL patients met our inclusion criteria. 97% were male. Majority were Non-Hispanic Whites (NHW 75%) followed by Non-Hispanic Blacks (NHB 12.5%), Hispanics (H 5.7%) and others (O 6.8%). NHB were diagnosed at younger median age (63 years) when compared to the NHW, H and O (68 years). There was no statistically significant difference in stage at diagnosis, IPI score, cell of origin (COO) and hit status amongst racial subgroups. Outcomes analysis (Table) revealed similar treatment and response rates, median OS, 1- and 2- year survival across all racial subgroups. However, after adjusting for age, IPI, COO, and exposure to agent orange, and including up to 10-years of survival data, H had 36% lower risk of death (HR=0.64, 95% CI 0.44-0.93) than NHW, while NHB and O had similar outcomes to NHW. Conclusions: This large retrospective study is a continuation of our group’s work (Williams et al, 2020) that doubles the cohort size and confirms that when standard of care therapy is given with equal access to care, short-term treatment and survival outcomes are same for all races. Further studies are needed to analyze risk factors associated with differences in long term outcomes.[Table: see text]